Pesticidal ear tag

ABSTRACT

Articles including eartags provide topical application of a mixture of (1) a macrolide of the avermectin/milbemycin class, such as, but not limited to ivermectin, abamectin, or milbemectin, and (2) a synergist of the aryl aliphatic ether-class, such as, but not limited to piperonyl butoxide, present in (3) a weight ratio of synergist:macrolide that is greater than 1:1. The articles are effective against various pests of domestic animals, including horn flies and buffalo flies.

CROSS-REFERENCE TO OTHER APPLICATIONS

This application is a continuation of U.S. patent Ser. No. 12/042,711filed Mar. 5, 2008, which is a continuation of International ApplicationNo. PCT/US2007/021243, filed Oct. 3, 2007 and designating the UnitedStates, which claims the benefit of U.S. Provisional Application No.60/947,265, filed Jun. 29, 2007. The disclosures of the aboveapplications are incorporated herein by reference.

FIELD

The present disclosure relates generally to pesticidal active ingredientcompositions and, more particularly, to compositions, methods anddevices containing or employing a mixture of at least oneavermectin/milbemycin-class compound, such as, but not limited toabamectin, ivermectin, or milbemectin, with a synergist, such aspiperonyl butoxide, which together provide an improved anti-pest effectas a toxicant against parasites of the group Ecdysozoa. The presentinvention can be particularly useful as an active ingredient compositionfor preventing or treating pest-infestation of animals, that can beapplied either topically or in a sustained release delivery system, suchas a resin base, for pest infestation control.

BACKGROUND

The statements in this section merely provide background informationrelated to the present disclosure and may not constitute prior art.Arthropods and their relatives are the most numerous of living organismsand nearly one million described species constitute approximately 70% ofall animal species. Of these, about 1% are considered significant pests.These pests attack humans and/or their domestic animals; transmit human,animal, and plant diseases; destroy structures; and compete foravailable supplies of food and other natural resources. In the UnitedStates, there are at least 600 species of such economically significantpests.

In an effort to control the damage done by various pests, there has beenwidespread use and development of pesticides. Pesticides are generallydefined as any substance or chemical designed or formulated to kill orcontrol weeds or animal pests. Pesticides directed against animal pestsinclude, e.g., insecticides, acaricides, helminthicides, molluscicides,and rodenticides, which are designed or formulated to either kill orcontrol, respectively: insects, mites or ticks, worms, mollusks, androdents. Generally, control is achieved by oral ingestion of stomachpoisons, contact with poisons that penetrate through the cuticle, orinspiration of fumigants that penetrate through the respiratory systemof the pest. Ancillary chemicals can also be employed in pest controland include attractants and repellants, which influence pest behavior,and chemosterilants, which influence reproduction. The control canpracticed to prevent pest infestation or to treat an existinginfestation, and the infestation can be of a type that is typicallyeither long-term (e.g., as with lice) or transitory (e.g., as withbiting flies).

The widespread use of chemical pesticides has resulted in increasingdifficulties in practical pest control. Examples of such difficultiesinclude: genetic selection under chemical pressure of strains of morethan 400 arthropod (insect and acarine) pests that are resistant to oneor more classes of pesticides and some to every available material;resurgences of pests and outbreaks of secondary pests that result fromelimination of natural enemies by the use of broad-spectrum pesticides;adverse human-health effects from injudicious use of highly toxicpesticides; and exponentially increasing costs of developing newpesticides.

One area of particular concern is the protection of domestic animals,such as cattle and other livestock, from parasites. Parasites can becontinuous or non-continuous, depending on whether the complete lifecycle, or only particular stage(s) of the life cycle, is host-based; andnon-continuous parasites can exhibit continually parasitic behaviorduring a particular life stage.

With respect to the protection of livestock and other domestic animals,significant advances have been made against previouslypesticide-resistant species of livestock ectoparasites. For example,horn flies (Haematobia irritans irritans), a non-continuousectoparasite, have been effectively controlled by the use of ear tagscontaining either pyrethroid or organophosphorus insecticides, includingmixtures of organophosphates such as diazinon (i.e., a pyrimidineorganothiophosphate) and chlorpyrifos (i.e., a pyridineorganothiophosphate), impregnated in a resin base, from which it can bereleased. The impregnation can be achieved by contacting the resin basearticle with an active ingredient composition according to the presentinvention, but in various preferred embodiments, the active ingredientcomposition can be present in admixture with the resin base componentsprior to forming an article therefrom The insecticide mixture is slowlyreleased from the resin base onto the skin (epidermis and/or hair) ofthe animal and exhibits good contact toxicity results with respect tovarious pests, including horn flies, stable flies, and ticks. A completediscussion of this technology can be found in commonly-assigned U.S.Pat. No. 5,472,955, the entire disclosure being incorporated herein byreference. An ear tag containing a mixture of diazinon and chlorpyrifosis readily commercially available from Y-Tex Corporation (Cody, Wyo.)and is being marketed under the trademark WARRIOR™.

Recently, another ear tag has been developed by Y-Tex Corporation and isbeing marketed under the trademark PYTHON®. This ear tag is similar tothe WARRIOR™ ear tag in that a synergized insecticide is impregnatedinto a resin base. However, the PYTHON® ear tag differs primarily fromthe WARRIOR™ ear tag in that the impregnated insecticide is an enrichedS-isomer, synthetic pyrethroid compound, as opposed to anorganothiophosphate compound. A synthetic pyrethroid compound isgenerally defined as a synthetic pesticide that mimics pyrethrin, theoriginal botanical pesticide derived from certain species ofchrysanthemum flowers. Examples of pyrethroid compounds include, withoutlimitation, allethrins, resmethrins, permethrins, and fenvalerates. Thesynthetic pyrethroids have the marked advantages of low to moderatetoxicity to humans and domestic animals and high effectiveness at lowapplication rates, often one-tenth of those required fororganophosphorus and carbamate insecticides. The PYTHON® ear tagutilizes zeta-cypermethrin (empirical formula: C₂₂H₁₉Cl₂NO₃) as theinsecticide. Zeta-cypermethrin (readily commercially available from FMCCorporation, Philadelphia, Pa.) is a mixture of stereoisomers comprisinghigh concentrations of s-isomers of cypermethrin. The zeta-cypermethrinis then combined with a synergist, such as piperonyl butoxide (empiricalformula: C₁₉H₃₀0₅), to produce a synergized insecticide. The PYTHON® eartag exhibits excellent contact toxicity against horn flies (includinghorn flies with moderate pyrethroid resistance), face flies (Muscaautumnalis), lice (Phthiraraptera order), Gulf Coast ticks (Ambylommamaculatum), and spinose ear ticks (Otobius megnini).

Other ear tags effective against certain ectoparasites are also readilycommercially available from Y-Tex Corporation and are marketed under thetrademarks OPTIMIZER® (containing diazinon and being generally effectiveagainst pyrethroid-resistant horn flies, face flies, Gulf Coast ticks,spinose ear ticks, and lice) and GARDSTAR® (containing permethrin andbeing generally effective against pyrethroid-susceptible horn flies,face flies, Gulf Coast ticks, spinose ear ticks, stable flies, houseflies, and lice).

Although the aforementioned insecticidal compositions have aided greatlyin the control and treatment of various livestock pests, someectoparasites, especially horn flies and buffalo flies (Haematobiairritans exigua), are now developing resistance to theseorganophosphorus- and/or pyrethroid-based insecticidal compositions.

As a result, there is a need to provide new or improved pesticidalcompositions of other chemical classes in order to allow alternation(i.e. rotation) of different types of pesticides so as to lessen theresistance, or decrease the rate of development of resistance, of localpest populations to any one of the pesticides included in a rotationprogram, and thereby provide effective whole-life treatment programs forlivestock and other animals. A need for alternative pesticidecompositions also arises because of variations in local pest speciespopulations, as by, e.g., introduction of foreign pests, changes due todiffering seasons or weather conditions, or by moves to differentenvironments, such as indoor-outdoor habitats, wetland-woodland-fieldhabitats, and geographic region habitats. Each of these factors canresult in a given pesticide composition's become less effective as aprotectant of the livestock or other treated animal, such that rotationwith another pesticide composition would be beneficial.

Thus, recent attention has focused toward pesticide compounds thatexhibit effectiveness against ectoparasites that have (or are)developing resistance to these organophosphorus- and/or pyrethroid-basedinsecticidal compositions. Among the compounds being actively developedare the pesticidal macrolides, which are a class of macrocyclic lactonesof the polypropionate-type polyketides. Of particular interest amongthese compounds are those classified as 16-member macrolides, i.e.having a 16-member macrocyclic lactone ring core. Among these arecompounds of the avermectin-milbemycin group, examples of which includethe abamectins, ivermectins, and milbemectins.

The currently available active ingredient compositions containing one ormore types of such macrolides, e.g., ivermectin, are delivered bywhole-animal drenching with a pour-on solution, by injection, or by oraladministration in relatively large doses. This is a difficult,time-consuming, and expensive undertaking for even a moderately sizedlivestock operation. Additionally, orally-administered activecompositions are sometimes very difficult to administer to anuncooperative animal, especially cattle, and may not be well toleratedby the animal's digestive system. Further, the orally-administeredcomposition may interfere with the animal's performance (e.g., weightgain or milk production) or may inadvertently poison the animal (e.g.,avermectin toxicosis). Also, the pest still has to bite the animal inorder to receive a toxic dose of an injected or orally administeredformulation. Finally, the enteral, parenteral, and topical drenchingroutes of administration induce a much higher concentration of pesticidein the animal tissues, resulting in the need to comply with a mandatorylivestock animal withdrawal period before slaughter, in order to permitmetabolic degradation and secretion of the pesticide. Thus, it would beadvantageous for all these reasons to provide a pesticidal macrolideformulation that is pesticidally effective, and that can be administeredin a less invasive or less pervasive manner, such as with an ear tag.Yet, pesticidal macrolides have been found to exhibit too low a level ofpesticidal contact activity to permit ear tag and other point-of-contactapplications to be feasible.

Therefore, there exists a need for a safe, effective, ready-to-use,pesticidal macrolide active ingredient composition and method of usethereof for the long-term prevention and treatment of pest/parasiteinfestation in domestic animals, especially cattle and other livestock,wherein the pesticide composition can be easily incorporated intotopical preparations and ear tags and which is effective against hornflies, buffalo flies and other ectoparasites, especially those that havedeveloped (or are developing) resistance to organophosphate- and/orpyrethroid-based insecticidal compositions.

SUMMARY

In accordance with one embodiment of the present invention, an ear tagcomprising an active ingredient composition is designed for attachmentto the ear of a domestic animal for the prevention and treatment of pestinfestation, as by pests of the group Ecdysozoa. The pest infestationcan be by pests of the phylum Arthropoda. Ectoparasitic infestation canthereby be treated, such as infestation by an arthropod ectoparasite.The active ingredient composition includes at least one avermectin ormilbemycin compound, such as, but not limited to abamectin, ivermectinor milbemycin. A synergist, preferably an aryl aliphatic ether such as,but not limited to piperonyl butoxide, is combined with the ivermectinor abamectin to produce a synergized active ingredient mixture. Thesynergized active ingredient mixture is then impregnated into a resinbase, such as, but not limited to polyvinyl chloride,acrylonitrile-butadiene copolymer, polyurethane, and chlorinatedpolyethylene, and then formed into the shape of an ear tag. The ear tagis then fastened to the ear of the animal in such a manner so as toallow the tag to physically contact various parts of the animal's body.The synergized active ingredient mixture is released from the tag overthe course of several months and is particularly effective againstvarious ectoparasites of domestic animals, such as, but not limited tohorn flies and buffalo flies.

Compositions according to the present invention have surprisingly beenfound capable of increasing the contact activity of these macrolidecompounds, and can thus make it feasible to utilizeavermectin/milbemycin-class macrolides, such as abamectin andivermectin, in formulations for long-lasting control of insect and otherpests. These compositions thereby permit the use of such macrolides tobe extended to the point-of-contact pesticide field (e.g., impregnatedear tags, impregnated “hang-tags” attached to another unit such as anidentification tag or halter, and spotting compositions such as spottingsolutions), in which they had not been otherwise found effective. Insome embodiments, by increasing the contact activity of the macrolide, atopical composition according to the present invention (e.g., a soak,rub, dip, spray, dust, or the like) can utilize a lesser concentrationof biocidal macrolide than would otherwise be the case.

In accordance with another embodiment of the present invention, atopically applied active ingredient composition is provided for theprevention and treatment of pest infestation. The active ingredientcomposition includes at least one avermectin compound, such as, but notlimited to ivermectin or abamectin. A synergist, such as, but notlimited to piperonyl butoxide technical is combined with the ivermectinor abamectin to produce a synergized active ingredient formulation. Thesynergized active ingredient formulation is then topically applied tovarious parts of the animal's body for example, as a pour-on, spot-on,dust, and the like.

The synergized active ingredient formulation is effective over thecourse of several weeks and is particularly effective against variousecdysozoan parasites of domestic animals, such as, but not limited tohorn flies and buffalo flies. The present invention further provides:

Ear tags capable of controlling pests of domestic animals, the tagsincluding a pesticidally effective amount of an active ingredientcomposition, impregnated in a polymer resin base from which it can bereleased, which composition contains (a) a macrolide componentcomprising an avermectin; and (b) a synergist component comprising a1,3-benzodioxole synergist compound; with (c) the weight ratio of thesynergist component (b) to the macrolide component (a) being greaterthan 1;

Such tags in which the avermectin can be an avermectin aglycone, anavermectin/milbemycin class derivative of the avermectin or aglycone, ora combination thereof; and/or in which the synergist component comprisespiperonyl butoxide;

Articles capable of controlling pests of domestic animals, the articlesincluding a pesticidally effective amount of an active ingredientcomposition, impregnated in a polymer resin base from which it can bereleased, which composition contains: (a) a macrolide componentcomprising a pesticidal compound of the avermectin-milbemycin class; and(b) a synergist component comprising a synergist compound; with (c) theweight ratio of the synergist component (b) to the macrolide component(a) being greater than 1;

Such articles in the form of a tag, collar, band, film, or adhesivestrip or patch.

Such articles in which the macrolide component comprises an avermectin;those in which the avermectin can be an avermectin aglycone, anavermectin/milbemycin class derivative of the avermectin or aglycone, ora combination thereof;

Such articles in which the synergist component comprises an arylaliphatic ether-class synergist compound; those in which the arylaliphatic ether-class synergist compound comprises any of the1,3-benzodioxole synergist compounds or combinations thereof, such aspiperonyl butoxide, piprotal, sesamex, sesamolin, piperonyl sulfoxide,bucarpolate, safrole, isosafrole, piperine, myristicin, apiole,dillapiole, dihydrodillapiole, or a combination thereof, e.g., piperonylbutoxide;

Active ingredient compositions capable of controlling pests of domesticanimals, the compositions containing: (a) a pesticidally effectiveamount of a macrolide component comprising a pesticidal compound of theavermectin-milbemycin class; and (b) a synergist component comprising asynergist compound; with (c) the weight ratio of the synergist component(b) to the macrolide component (a) being greater than 1;

Such compositions in the form of a spotting solution, a soak, rub, dip,spray, dust, or other topical formulation, or is comprised by apolymeric material from which it can be released;

Such compositions in which the macrolide component comprises anavermectin; those in which the avermectin can be an avermectin aglycone,an avermectin/milbemycin class derivative of the avermectin or aglycone,or a combination thereof;

Such compositions in which the synergist component comprises an arylaliphatic ether-class synergist compound; those in which the arylaliphatic ether-class synergist compound comprises any of the1,3-benzodioxole synergist compounds or combinations thereof, such aspiperonyl butoxide, piprotal, sesamex, sesamolin, piperonyl sulfoxide,bucarpolate, safrole, isosafrole, piperine, myristicin, apiole,dillapiole, dihydrodillapiole, or a combination thereof, e.g., piperonylbutoxide;

Methods for controlling pest infestation of domestic animals, involving(I) providing (A) a pesticidally effective amount of an activeingredient composition containing (1) a macrolide component comprising apesticidal compound of the avermectin-milbemycin class; and (2) asynergist component comprising a synergist compound; with (3) the weightratio of the synergist component (b) to the macrolide component (a)being greater than 1; or (B) an article comprising a pesticidallyeffective amount of said composition impregnated in a polymer resin basefrom which it can be released; and (II) applying the composition orarticle to an external body surface of a domestic animal;

Such methods in which the macrolide component comprises an avermectin;those in which the avermectin can be an avermectin aglycone, anavermectin/milbemycin class derivative of the avermectin or aglycone, ora combination thereof;

Such methods in which the synergist component comprises an arylaliphatic ether-class synergist compound; those in which the arylaliphatic ether-class synergist compound comprises any of the1,3-benzodioxole synergist compounds or combinations thereof, such aspiperonyl butoxide, piprotal, sesamex, sesamolin, piperonyl sulfoxide,bucarpolate, safrole, isosafrole, piperine, myristicin, apiole,dillapiole, dihydrodillapiole, or a combination thereof, e.g., piperonylbutoxide;

Such methods in which the pest is an arthropod ectoparasite, such as amember of the horn flies, Haematobia irritans irritans, or buffaloflies, Haematobia irritans exigua.

A more complete appreciation of the present invention and its scope canbe obtained from the following detailed description of the invention,and the appended claims.

DRAWINGS

The drawings described herein are for illustration purposes only and arenot intended to limit the scope of the present disclosure in any way.

FIG. 1 presents a graph of test results for control of horn flies(Haematobia irritans irritans) on beef cattle using ear tags impregnatedwith a composition according to an embodiment hereof, versus usingcommercially available ear tags: ▪ WARRIOR ear tag comprising theorganophosphate insecticides, diazinon and chlorpyrifos; ▴ PYthon eartag comprising the synthetic pyrethroid insecticide, zetacypermethrin,plus piperonyl butoxide; and ♦ Present Embodiment of ear tag comprisingabamectin plus piperonyl butoxide.

DETAILED DESCRIPTION

The following description of technology is merely exemplary in nature ofthe subject matter, manufacture and use of one or more inventions, andis not intended to limit the scope, application, or uses of any specificinvention claimed in this application or in such other applications asmay be filed claiming priority to this application, or patents issuingtherefrom. The following definitions and non-limiting guidelines must beconsidered in reviewing the description of the technology set forthherein.

The headings (such as “Background “Summary,”) and sub-headings (such as“Articles”) used herein are intended only for general organization oftopics within the disclosure of the invention, and are not intended tolimit the disclosure of the invention or any aspect thereof. Inparticular, subject matter disclosed in the “Field” and “Background” mayinclude aspects of technology within the scope of the invention, and maynot constitute a recitation of prior art. Subject matter disclosed inthe “Summary” is not an exhaustive or complete disclosure of the entirescope of the invention or any embodiments thereof.

The citation of references herein does not constitute an admission thatthose references are prior art or have any relevance to thepatentability of the invention disclosed herein. Any discussion of thecontent of references cited in the Introduction is intended merely toprovide a general summary of assertions made by the authors of thereferences, and does not constitute an admission as to the accuracy ofthe content of such references. All references cited in the Descriptionsection of this specification are hereby incorporated by reference intheir entirety.

The description and specific examples, while indicating embodiments ofthe invention, are intended for purposes of illustration only and arenot intended to limit the scope of the invention. Moreover, recitationof multiple embodiments having stated features is not intended toexclude other embodiments having additional features, or otherembodiments incorporating different combinations of the stated features.Specific Examples are provided for illustrative purposes of how to make,use and practice the compositions and methods of this invention and,unless explicitly stated otherwise, are not intended to be arepresentation that given embodiments of this invention have, or havenot, been made or tested.

In accordance with a preferred embodiment of the present invention, aneffective amount of at least one avermectin or milbemycin, such as, butnot limited to abamectin, ivermectin, milbemectin, is employed as atopically applied active ingredient composition. In accordance with ahighly preferred embodiment of the present invention, a mixture of atleast one avermectin, such as, but not limited to ivermectin orabamectin, and a synergist, such as, but not limited to piperonylbutoxide (preferably technical grade) in ratios of about one partivermectin or abamectin and about at least two parts piperonyl butoxide,is provided as a synergized active ingredient composition. Such acombination has been found to exhibit a surprisingly high level ofeffectiveness against pest infestations of animals, including cattle andother livestock. In particular, effectiveness has been found againstvarious ecdysozoan pests, e.g., arthropod parasites.

The synergized active ingredient compositions of the present inventiondemonstrate a surprising increase in contact toxicity against Haematobiairritans species (e.g., horn flies and buffalo flies) and other domesticanimal ectoparasites, including populations resistant to pyrethroids andorganophosphates, making it more feasible to utilize avermectins such asivermectin or abamectin, or milbemycins such as milbemectin, informulations for long-lasting control of these pests. Examples of otherecdysozoan pests, e.g., ectoparasites, that may be controlled therebyinclude various lice, mites, and keds, and other species.

Synergized active ingredient compositions according to the presentinvention exhibit oil solubility and releasability from a resin base.The resin base can form an animal tag, such as an ear tag or a hang tag.Such ear tags have been unexpectedly found to provide, through the smallamount of contact between the tag and the animal's skin, a sufficientdose of the avermectin or milbemycin to effectively treat parasiticinsect infestations.

Avermectins and Milbemycins

Members of the avermectin/milbemycin class of compounds act byinterfering with gamma aminobutyric acid (GABA), a neurotransmitter thatis only found as a peripheral neurotransmitter in invertebrate pests,e.g., insects, but that in mammals is found only in the brain.Specifically, compounds of this class, such as abamectin, ivermectin,and milbemectin, have been found to bind selectively with strongaffinity to GABA-gated, glycine-gated, or glutamate-gated chloride ionchannels which occur in invertebrate nerve and muscle cells. This leadsto increased permeability of the cell membranes to chloride ions whichleads to hyperpolarization of the nerve or muscle cell, resulting inparalysis and eventual death of the pest.

The naturally occurring avermectins and milbemycins are 16-membermacrolides containing a spiro-ketal group: the 16-member core macrocycle

fused to a 6,6-spiroketal group and is also separately fused to afurther additional ring or ring system that is a single ring (acyclohexene or benzene ring) or a bi-cyclic ring system (ahexahydrobenzofuran ring system); the core macrocycle of these compoundsfurther comprises a conjugated diene. The resulting tetra- orpenta-cyclic unit can be isolated in a glycone form, from variousStreptomyces spp. cultures. These features are illustrated in formula(I).

A number of exemplary members of the avermectin-milbemycin group, whichare useful in various embodiments hereof, are shown in Table 1, withreference to formula (1).

TABLE 1 Exemplary Avermectin-Milbemycin Group Members NAME X-Y —OR1 R2R3 Notes Avermectin A1a CH═CH —OCH3 [O]2 sec-Butyl Avermectin A1b CH═CH—OCH3 [O]2 iso-Propyl Avermectin A2a CH₂—CH(OH) —OCH₃ [O]2 sec-ButylAvermectin A2b CH₂—CH(OH) —OCH₃ [O]2 iso-Propyl Avermectin B1a CH═CH —OH[O]2 sec-Butyl Abamectin (~80%) Avermectin B1b CH═CH —OH [O]2 iso-PropylAbamectin (~20%) Avermectin B2a CH₂—CH(OH) —OH [O]2 sec-Butyl AvermectinB2b CH₂—CH(OH) —OH [O]2 iso-Propyl Avermectin H2B1a CH₂—CH₂ —OH [O]2sec-Butyl Ivermectin (~80%) Avermectin H2B1b CH₂—CH₂ —OH [O]2 iso-PropylIvermectin (~20%) Doramectin CH═CH —OH [O]2 Cyclohexyl SelamectinCH₂—CH₂ ═NOH [O] Cyclohexyl Emamectin B1a CH═CH —OH M[O]2 sec-ButylEmamectin (~80%) Emamectin B1b CH═CH —OH M[O]2 iso-Propyl Emamectin(~20%) Eprinomectin B1a CH₂—CH₂ —OH A[O]2 sec-Butyl Eprinomectin (~80%)Eprinomectin B1b CH₂—CH₂ —OH A[O]2 iso-Propyl Eprinomectin (~20%)Milbemycin A3 CH₂—CH₂ —OH H Methyl Milbemectin (~20%) Milbemycin A4CH₂—CH₂ —OH H Ethyl Milbemectin (~80%) Milbemycin B CH₂—CH₂ —OCH₃ H HOpen THF: Chxene + C8(CH₂OH) Milbemycin D CH₂—CH₂ —OH H iso-PropylMilbemycin E CH₂—CH₂ —OCH₃ H iso-Propyl Open THF: Chxene + C8(CH₂OH)Milbemycin G CH₂—CH₂ —OCH₃ H iso-Propyl Milbemycin A3 Oxime CH₂—CH₂ ═NOHH Methyl Milbemycin Oxime (~20%) Milbemycin A4 Oxime CH₂—CH₂ ═NOH HEthyl Milbemycin Oxime (~80%) Milbemycin Alpha-2 CH₂—CH₂ —OCH₃ H MethylMilbemycin Beta-1 CH₂—CH₂ —OCH₃ H Methyl Open THF: Chxene + C8(CH₂OH)Milbemycin Beta-3 CH₂—CH₂ —OH H Methyl Open THF: Bzene + C8(CH₃)Milbemycin K CH₂—CH₂ —OCH₃ H Ethyl Moxidectin CH₂—C(═NOH) —OH H 1,3dimethylbutenyl Nemadectin CH₂—CH(OH) —OH H 1,3 dimethylbutenylLepimectin A3 CH₂—CH₂ —OH MIPA Methyl Lepimectin (~20%) Lepimectin A4CH₂—CH₂ —OH MIPA Ethyl Lepimectin (~80%) Notes: “═NOH” indicatessubstitution with a hydroxyimino group; at C5 this replaces the hydroxylor alkoxyl. “[O]2” indicates that C13 is substituted with adi-oleandrosyl group. “M[O]2” indicates that C13 is substituted with a4″-deoxy-4″methylamino-di-oleandrosyl group. “A[O]2” indicates that C13is substituted with a 4″-deoxy-4″acetylamino-di-oleandrosyl group. “[O]”indicates that C13 is substituted with a mono-oleandrosyl group. “OpenTHF: Chxene + C8(CH₂OH)” indicates that, compared to formula (1), thenamed compound has a structure equivalent to one in which thetetrahydrofuran ring of the depicted fused hexahydro-benzofuran systemis opened, leaving a fused cyclohexene ring of C2-C7 and, at C8, ahydroxymethyl substituent. “Open THF: Bzene + C8(CH₃)” indicates that,compared to formula (1), the named compound has a structure equivalentto one in which the tetrahydrofuran ring of the depicted fusedhexahydro-benzofuran system is opened and deoxidated, and that the fusedcomponent is also tetradehydro, thereby leaving a fused benzene ring ofC2-C7 and, at C8, a methyl substituent. “MIPA” indicates that C13 issubstituted with a [(methoxyimino)phenylacetyl]oxy group.

In naturally occurring or commonly prepared avermectin compound a/bpairs, e.g., mixed avermectin B1a/B1b pairs, and derivatives of suchmixed pairs, e.g., ivermectin, the ratio (a:b)>1 is typically found,with the larger compound being the major component. In naturallyoccurring or commonly prepared milbemcyin compound pairs, e.g., mixedmilbemectin A3/A4 pairs, and derivatives of such mixed pairs, e.g.,milbemycin oxime, the ratio (A4:A3)>1 is typically found, with thelarger compound being the major component. Approximately 80:20 ratiosare common and are useful herein in some embodiments; in someembodiments, a composition comprising such compounds in at least a60:40, 70:30, 75:25, or 80:20 ratio can be used.

The avermectins are a series of compounds possessing anthelmintic andantiparasitic activity that include both naturally occurring compoundsas well as derivatives and analogs that were developed based on thestructures of the original avermectin natural products. These naturalproducts were first isolated as a complex from a fermentation broth ofan actinomycete strain, Streptomyces avermitilis, and described in U.S.Pat. No. 4,310,519 to Albers-Schonberg et al., the entire specificationof which is incorporated herein by reference. The naturally occurringavermectin complex includes four closely related major components,designated A1a, A2a, B1a, and B2a, and four minor components, designatedA1b, A2b, B1 b, and B2b, which are respectively lower homologs of thecorresponding major components.

Such naturally occurring avermectin-type compounds are typically foundin their glycone form, being glycosylated at C13; and the most commonglycosylation thereof is C13 linkage to a dioleandrosyl group:alpha-L-oleandrosyl-1″-O→4′-alpha-L-oleandrosyl-1′-O-yl. The B1a/B1bavermectins are the most preferred pair with respect to antiparasiticapplications, and an approximately 80:20 mixture thereof is known asabamectin. Some avermectins have been produced as 22,23-dihydroderivatives, such as those described in U.S. Pat. No. 4,199,569 toChabala et al., the entire disclosure of which is incorporated herein byreference. In some embodiments in which a 22,23-dihydro avermectin isused, 22,23-dihydro avermectin B1a or B1b can be used; in some suchembodiments, a combination, e.g., an approximately 80:20 mixture, ofboth of these compounds can be used. Such a mixture is also known asivermectin. Similarly, milbemycins include natural products andderivatives thereof that are based on such naturally occurringstructures; and 80:20 A4:A3 ratios of compound pairs, e.g., milbemectin,milbemycin oxime, and lepimectin, are also considered useful in somemilbemycin-containing embodiments hereof.

Thus, both naturally occurring avermectins and milbemycins, andbiotransformed or semisynthetic derivatives of these compounds, as wellas synthetic compounds having structures equivalent thereto, all ofwhich belong to the avermectin-milbemycin class and exhibit antipestactivity, are useful in various embodiments hereof. For example,milbemycin B-41D, milbemycin J, latidectin, O-demethyl selamectin;hydroxyl-selamectin, alpha- and beta-milbemycins, and milbemycinglycones can be used.

New avermectin and milbemycin derivatives can be prepared bymodification of an already existing avermectin or milbemycin compound,such as by enzymatic modification, e.g., microbial biotransformation, orby chemical modification thereof. Such compounds, which exhibit antipestactivity, are useful in various embodiments of the present invention.Various derivatives include those described in, e.g., U.S. Pat. No.4,831,016 to Mrozik et al., U.S. Pat. No. 4,916,120 to Roben et al.,U.S. Pat. No. 4,927,847 to Dutton et al., U.S. Pat. No. 4,945,105 toSato et al., U.S. Pat. No. 5,008,191 to Okazaki et al., U.S. Pat. No.5,015,630 to Fisher et al., U.S. Pat. No. 5,023,241 to Linn et al., U.S.Pat. No. 5,030,622 to Mrozik et al., U.S. Pat. No. 5,055,454 to Blizzardet al., U.S. Pat. No. 5,055,596 to Baker et al., U.S. Pat. No. 5,077,308to Blizzard, U.S. Pat. No. 5,089,480 to Gibson et al., U.S. Pat. No.5,114,930 to Blizzard et al., U.S. Pat. No. 5,122,618 to O'Sullivan,U.S. Pat. No. 5,169,839 to Linn et al., U.S. Pat. No. 5,177,063 toMeinke, U.S. Pat. No. 5,208,222 to Meinke et al., U.S. Pat. No.5,240,915 to Rosegay, U.S. Pat. No. 5,262,400 to Chu et al., U.S. Pat.No. 5,350,742 to Meinke et al., U.S. Pat. No. 5,411,946 to Newbold etal., U.S. Pat. No. 5,478,929 to Arison et al., U.S. Pat. No. 5,556,868to Banks, U.S. Pat. No. 5,614,470 to Takeshiba et al., U.S. Pat. No.5,830,875 to Mrozik et al., U.S. Pat. No. 5,840,704 to Gibson et al.,U.S. Pat. No. 5,883,080 to Dutton et al., U.S. Pat. No. 5,981,500 toBishop et al., and U.S. Pat. No. 6,605,595 to Omura et al. Thederivatives of the macrocylic ring systems described therein can be usedin various glycone or aglycone embodiments hereof, and the derivativesof the oleandrosyl or other glycosyl moieties thereof can beindependently used in various glycone embodiments hereof.

Useful derivatives in the avermectin-milbemycin class include those16-member macrolides in which the fused benzofuran, benzene, orcyclohexene ring is replaced with another fused, homo- orhetero-hydrocarbon cycloaliphatic or aromatic ring or fused ring systemhaving from 3 to about 8 ring carbon atoms (single ring) or from about 6to about 15 ring carbon atoms (fused ring systems); in variousembodiments, such fused ring systems can contain up to 5, preferably upto 4, or 3 or 2 fused rings. Rings and fused ring systems can becycloaliphatic or aromatic. Useful avermectin-milbemycin derivativesalso include those 16-member macrolides in which the fused6,6-spiroketal ring system can be replaced with another spiro ringsystem, such as another 6,6-spiro or a 6,5-, a 5,6-, or a 5,5-spirosystem. Some preferred examples of spiro ring systems includespiroether, spiroester, or spirolactone (e.g., spirolactide) ringsystems, with those systems that contain two or at least two oxa ringatoms, preferably at least one oxa per ring or preferably at most 2 oxasper ring, being considered particularly useful. Spiro(bis)ether ringsystems, such as spiroketal or spiroacetal ring systems, preferably6,6-spiro(bis)ethers, can be used. In some embodiments, both the fusedbenzofuran/benzene/cyclohexene ring can be replaced and the fusedspiroketal ring system can be replaced, as described. The resultingderivatives have so far been described in terms of aglycone forms ofsuch avermectin-milbemycin class members. Yet, glycones and othersubstituted variants of these polycyclic aglycones are also usefulhereon.

Examples of substituted variants of aglycones hereof are those thatcomprise any one or more of the following substituents: hydroxy, alkoxy,acyloxy groups; hydroxy-, alkoxy-, acyloxy-alkyl groups; hydroxyimino(i.e. oxime), alkoxyimino groups; oxo; sulfur-containing (thia or thio)analogs of the foregoing groups; halo groups; and nitrogen-containinggroups, e.g. amino, cyano, imino, amido, or imido groups, alkyl-amino,-imino, -amido, or -imido groups.

Referring to formula (I), in some embodiments hereof, —OR1 can comprise6 or fewer carbon atoms, and in some embodiments can be hydroxy,methoxy, ethoxy, hydroxyimino, methoxyimino, or ethoxyimino, withhydroxy, methoxy, and hydroxyimino being considered particularly usefulin some embodiments. Also, referring to formula (1), R3 can be a C1 toC8 alkyl substituent in various embodiments, preferably a methyl, ethyl,propyl, propenyl, butyl, or butenyl group or a saturated or unsaturatedcyclic group.

In various embodiments, the aglycone or substituted aglycone moiety ofthe compound can also have a saccharide substituent. A saccharidesubstituent can be a mono- or polysaccharide; among polysaccharidesubstituents, di-, tri-, and tetra-saccharides are preferred, and di-and tri-saccharides are considered particularly useful is someembodiments. In various embodiments, mono- and di-saccharides areparticularly preferred. A saccharide substituent can be attached at C13,or at another position; C13 is a preferred location for glycosylation inglycosylated compounds hereof. In various embodiments, an aglycone orsubstituted aglycone can contain one or more saccharide substituents,with singly glycosylated compounds being preferred glycosylatedcompounds for use herein.

Monosaccharide residues of a saccharide substituent can be any of: thealdo- or keto-hexoses, -pentoses, -tetroses, or -heptoses, with hexosesand pentoses being considered particularly useful, and hexosesparticularly preferred, in some embodiments; or deoxy cognates thereof.In some embodiments of glycones, monosaccharide residues of thesaccharide substituent can be modified monosaccharide residues, i.e.saccharides having as substituents, e.g.: alkyl, alkoxy, acyl, acyloxygroups; alkoxy-, acyl-, acyloxy-alkyl groups; oxo; sulfur-containing(thia or thio) analogs of these; or organic nitrogen-containing groups,e.g. amino, imino, amido, or imido groups, alkyl- or acyl-amino, -imino,-amido, or -imido groups, and the like. In various embodiments,non-sulfur-containing monosaccharide residues are preferred. In someembodiments, a compound for use herein can contain a mono- ordi-oleandrosyl substituent at C13 of the aglycone moiety; in someembodiments, the oleandrosyl substituent can be a modified oleandrosylsaccharide group. Other specific examples of useful monosaccharideresidues include olivose, cladinose, and desosamine. In some embodimentsof di- and greater saccharides, the monosaccharide residues thereof canbe the same or different.

Specific examples of aglycone substitutions found in some avermectins ormilbemycins include, e.g.: C5 substitution with hydroxylimino, alkoxy,oxo, or alkoxylimino group(s); C13 substitution with hydroxy, alkoxy, oracyloxy group(s), hydroxy-, alkoxy-, or acyloxy-alkyl group(s); mono-and poly-saccharides including amino sugars, alkylamino sugars,acylamino sugars, and the like; or C13 substitution with other cyclicgroups, e.g., aryl-acyl and aryl-acyloxy groups, such as 2-[4-(2-alkyoxyacetamido)phenyl]-cyclopentanoyloxy groups; C23 substitution withhydroxy, hydroxylimino groups; C26 substitution with alkoxy groups,e.g., 3-methyl-2-butenoyloxy; C27 substitution with oxo or halo, e.g.,fluoro; C28 substitution with hydroxy; and C29 substitution hydroxy ordihydroxy.

In the above substituent groups for the aglycone, “alkyl” refers to any(homo- or hetero-) aliphatic and/or cycloaliphatic group, preferablycontaining 18 or fewer carbon atoms, or 15, 12, 10, 8, or 6 or fewercarbon atoms. Similarly, “acyl” in regard to such substituents refers toradicals of carboxylic acids comprising such an alkyl group attached toa carbonyl carbon of the acid. Esters of acid, e.g., acyl, groupspresent in a compound hereof can be provided in the form of alkyl estersthereof. Compounds hereof can likewise be provided in the form of a saltin various embodiments. Epimers of a member of the avermectin-milbemycinclass are also useful herein, e.g., C12-epi or C13-epi compounds.

Compounds hereof also include the physiologically acceptable salts andcomplexes of avermectin-milbemycin class compounds, such as any of theacid addition or other salts that are commonly used in veterinary orhuman pharmaceutical practice. These include, e.g., aromatic andaliphatic mono-, di-, and tri-carboxylic acids, such as amino acids,benzoates, acetates, etc., and those described in P. H. Stahl and C. G.Wermuth, editors, Handbook of Pharmaceutical Salts: Properties,Selection and Use (2002) (Wiley-VCH/VHCA, Weinheim/Zürich), and thoseotherwise known in the art. Thus, e.g., emamectin-benzoate can be usedin various embodiments hereof.

In various embodiments, compounds of the avermectin-milbemycin class,including avermectin/milbemycin derivatives, can have an octanol-waterpartitioning coefficient (logPow) value that is about 3.5 or more, orabout 4 or more; in some embodiments at least 3.5 or at least 4; andpreferably more than 4. In some embodiments, the logPow value can beabout 8 or less. Such logPow values can be assessed by an analyticalchemistry technique, or estimated using, e.g., QSAR algorithmcalculations. Calculated logPow value estimates can be performed, e.g.,using a publicly available program such as the ALOGPS software availableon-line at the World Wide Website (.vcclab.org/lab/alogps/) of theVirtual Computational Chemistry Laboratory of the Institut fürBioinformatik of the GSF-Forschungszentrum für Umwelt and Gesundheit,GmbH (Munich, DE). Any analytical chemistry method known for determininglogPow values greater than zero can be used, such as by analysis atabout pH7.2, at room temperature or about 25° C., according to aprocedure such as

described, e.g., in U.S. Pat. No. 7,074,785 to Seitz et al., or in ASTME1147-92, or by a shake-flask (or tube) phase separation method using anequilibrated water-octanol system.

In various embodiments, compounds of the avermectin-milbemycin class,including avermectin/milbemycin derivatives, can have a molecular weightfrom about 400 to about 2500. In various embodiments, compounds of theavermectin-milbemycin class, including avermectin/milbemycinderivatives, comprise a polycyclic macrolide aglycone moiety that has amolecular weight of about 1500 or less, 1200 or less, 1000 or less; ofabout 400 or more, 500 or more, 600 or more, or 700 or more; and invarious preferred embodiments from about 450 to about 900, about 450 toabout 800, about 450 to about 700, or about 450 to about 600. In variousembodiments in which the aglycone is substituted, the compound can havea molecular weight of at least or about 450, 500, 550, or 600; of about2500 or less, or less than or about: 2250, 2000, 1750, 1500, 1250, or1000. In some preferred embodiments, the compound can have a molecularweight of about 450 to about 1000.

Many types of pesticidal derivatives of the avermectins and milbemycinsthat fall within the avermectin/milbemcyin class of pesticides aredescribed in scores of patent documents and many more journal articles;these are also useful in various embodiments of the present invention.

Pesticidal activity of a given derivative can be assessed by use of anymethod known in the art, such as by exposing sets of arthropod adults orlarvae to the compound at one or more concentration level(s) anddetermining the number of survivors compared to untreated controls.Rapids methods such as those described in U.S. Pat. No. 5,583,008 toJohnson et al., can be used.

In various embodiments, an avermectin can be used in or as the macrolidecomponent of the (synergized) active ingredient composition. In someembodiments, this can be any one or more of: avermectin A1a, avermectinA1b, avermectin A2a, avermectin A2b, avermectin B1a, avermectin B1 b,avermectin B2a, or avermectin B2b; aglycones thereof;avermectin/milbemycin class derivatives of any of these; andcombinations of the foregoing. In some preferred embodiments, theavermectin can comprise a combination of avermectin B1a and avermectinB1b or an avermectin/milbemycin class derivative or combination ofavermectin/milbemycin class derivatives thereof, preferably in which theweight ratio of avermectin B1a or the B1a-derivative to avermectin B1bor the B1b-derivative is greater than 1. Among the avermectins,abamectin and ivermectin are considered particularly useful. In somepreferred embodiments, the macrolide component can comprise abamectin.

One or more than one pesticidal macrolide hereof can be used in someembodiments of the present invention. In some embodiments otherpesticidal active(s) can also be included. Combinations of pesticidalmacrolides useful herein include the mixed a/b avermectins, the mixedA3/A4 milbemycins, avermectin/milbemycin combinations, and others, e.g.,those described in U.S. Pat. No. 4,560,677 to Dybas.

Synergists

As noted above, active ingredient compositions here comprise both amacrolide component and a “synergist.” In the field of pest control,synergists are a class of compounds that can enhance the pesticidalactivity of the pesticidal composition, in some cases by exerting anindependent pest toxifying effect, by inhibiting a pesticide-degradingenzymatic activity of the pest, or by some other route.

A wide variety of pesticide synergist compounds of different chemicalclasses are known and these include, e.g.:

1. The alkynylpolyarene synergists, such as C2-C6 alkynyl-anthracenes,-pyrenes, -flavones, -biphenyls, and the like, see, e.g., J. G. Scott etal., Pesticide Biochem. & Physiol. 67:63-71 (2000);

2. The substituted N-aromatyl imines, such as1-(1-((4-Chloro-2-(trifluoromethyl)phenyl)imino)-2-propoxyethyl)-1H-imidazole(Triflumizole);

3. The dicarboximide synergists, such asN-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide, n-octylbicycloheptene dicarboximide;

4. The aryl alkylamine ether and ester synergists, such as2-((4,6-dichloro-2-biphenylyl)-oxy) triethylamine, 2-(diethylamino)ethyl2,2-diphenyl pentanoate;

5. The aminopyridine synergists, such as 2-aminopyridine,3-aminopyridine;

6. The organothiocyanate synergists, such as p-nitrobenzyl thiocyanate;

7. The organophosphoxy ester synergists, preferably non-insecticidalmembers, such as (1) organic thiophosphates, e.g.,O-(4-bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothioate(Profenofos); (2) organic phosphonothionates, e.g.,O-ethyl-O-p-nitrophenyl phenylphosphonothionate (EPN); (3) organicphosphorothioates (carbamates), preferably non-insecticidal carbamates;and (4) trisubstituted aliphatic and aromatic phosphates, e.g.,tri-o-cresyl phosphate (TOCP), triphenyl phosphate (TPP),S,S,S-tributylphosphorotrithioate (DEF),O,O-disopropyl-5-benzylthiophosphate (IBP);

8. The bis(polyhalogenated aliphatic) ether synergists, e.g.,2,3,3,3,2′,3′,3′,3′-octachlorodipropyl ether (S-421);

9. The aryloxyalkylamine synergists, such as 3-diethylaminoethyldiphenylpropylacetate;

10. The formamidine synergists, such asN′-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl)imino]methyl]-N-methylmethanimidamide(Amitraz); N-(2-(4-chloro toluenyl)-imine (Chlordimeform);

11. The plant oil synergists, e.g.: sesame, neem, castor, soybean,coconut, canola, mustard, palm, citronella, and karanj (Pongamia pinnataseed) oils;

12. Various substituted aryl alcohol, acid, and ester synergists, suchas 1,1-di(p-chlorophenyl)-2,2,2-trifluoroethanol (F-DMC);(1,1-bis(4-chlorophenyl)ethanol (Chlorofenethol; BCPE); diethyl maleate(DEM); and [(5-chloro-8-quinolinyl)oxy]acetic acid, 1-methylhexyl ester;and

13. The aryl aliphatic ether synergists, i.e. aliphatic ethers of arylor alkylaryl rings.

Among this wide spectrum of synergists, the aryl aliphatic ethersynergist class has been unexpectedly found to substantially enhance thecontact activity of pesticidal avermectin/milbemycin class macrolidecompounds. As a result, an active ingredient composition hereofpreferably contains an aryl aliphatic ether synergist.

Examples of useful aryl aliphatic ether-class synergists herein includethe methylenedioxyarene and the alkynyloxyarene types. Representativeexamples of these synergist types are set forth below.

A) Methylenedioxyarene synergists, e.g., methylenedioxynaphthalene andmethylenedioxyphenyl (MDP) synergists, preferably MDP synergists;examples of methylenedioxyarene synergists including (1) benzodioxolesynergists, such as5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-benzodioxole (Piperonylbutoxide); 5-(bis[2-(2-butoxyethoxy)ethoxy]methyl)-benzodioxole(Piprotal); 5-(1-[2-(2-ethoxyethoxy)ethoxy]ethoxy)-benzodioxole(Sesamex);5-[4-(benzodioxol-5-yloxy)tetrahydro-1H,3H-furo[3,4-c]furan-1-yl]-benzodioxole(Sesamolin); 5-[2-(octylsulfinyl)propyl]-benzodioxole (Sulfoxide;piperonyl sulfoxide); 2-(2-butoxyethoxy)ethyl piperonylate(Bucarpolate); 5-(2-propenyl)-benzodioxole (Safrole);5-(1-propenyl)-benzodioxole (Isosafrole);1-[5-(benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine (Piperine);4-methoxy-6-(2-propenyl)-benzodioxole (Myristicin);4,7-dimethoxy-5-(n-prop-2-enyl)-benzodioxole (Apiole);4,5-dimethoxy-6-(n-prop-2-enyl)-benzodioxole (Dillapiole);5-(n-propyl)-6,7-dimethoxy-benzodioxole (dihydrodillapiole); (2)methylenedioxynaphthalene synergists, such as dipropyl5,6,7,8-tetrahydro-7-methylnaphtho[2,3-d]-dioxole-5,6-dicarboxylate(Propyl isome); and 2,3-methylenedioxynaphthalene; and (3) alkynyl- andalkynyloxy-methylenedioxyarene synergists, preferably alkynyl- andalkynyloxy-methylenedioxyphenyl synergists, preferably in which thealkynyl group(s) is a C2-C6 alkynyl group (preferably at least C3,preferably up to C4; preferably those in which the alkynyl group is orcomprises a 2-yne or 3-yne), such as alkynyloxy benzodioxoles, e.g.,5-[(2-butynyloxy)-isopropyl]benzodioxole (Verbutin). (Where benzodioxoleis referred to herein, it is preferably 1,3-benzodioxole.)

B) Alkynyloxyarene synergists, preferably C2-C6 alkynyloxyarenesynergists (preferably at least C3, or up to C4, and particularly C3),preferably those in which the alkynyl group is or comprises a 2-yne or3-yne, such as: (1) substituted phenyl-oxy-2-alkynyl ethers, e.g.,2,6-Dichlorobenzyl-2-propynyl ether,2,3,6-trichloro-3(2-propynyloxy)benzene (TCPB),2-propynyl-4-chloro-2-nitrophenyl ether,O-n-Propyl-O-(2-propynyl)phenylphosphonate; (2) N-alkynyloxy imines andimides comprising aromatic ring(s), e.g., N-(propargyloxy) phthalimide;and (3) others, see, e.g., U.S. Pat. No. 6,320,085, and US PublicationNo. 2005/038082A1.

An ether group of such ethers can comprise an oxo-ether or thio-etherlinkage; in various preferred embodiments, this can be an oxo-etherlinkage. Among these compounds, methylenedioxyarene synergists areconsidered particularly useful. In various embodiments, the synergistcan be any one or more of the methylenedioxyphenyl ormethylenedioxynaphthalene synergists. In various embodiments, amethylenedioxyphenyl synergist can be used; in some preferredembodiments, this can be a benzodioxole synergist, preferably a1,3-benzodioxole synergist. Useful examples of 1,3-benzodioxolesynergist include, e.g., piperonyl butoxide, piprotal, sesamex,sesamolin, piperonyl sulfoxide, bucarpolate, safrole, isosafrole,piperine, myristicin, apiole, dillapiole, dihydrodillapiole, andcombinations thereof. In some embodiments, the synergist component cancomprise piperonyl butoxide (PBO). PBO can be provided in the form ofpure PBO or in the form of, e.g., PBO “technical grade” which containsabout 90% by weight PBO.

In various embodiments, alkyl/aliphatic group(s) of a synergist cancomprise from 1 to about 18 carbon atoms. In various embodiments, arylgroup(s) of a synergist can comprise from 3, 4, 5, or 6 to about 18carbon atoms.

Active Ingredient Compositions

An active ingredient composition hereof comprises both a macrolidecomponent and a “synergist.” The compound(s) of each of these componentscan be mixed together to form the composition, or these compounds can beindependently added to another component, e.g., a particle for use inpreparing a dust, an organic solvent for use in preparing a spotting orother solution; or a resin or other matrix material. Examples of usefulsolvents include isopropanol and other alkyl alcohols, and organicsolvents at least as hydrophobic as isopropanol, examples of whichinclude topically acceptable: oils, e.g., biological oils,petroleum-derived oils (e.g., mineral oil), synthetic oils; polyols(e.g., glycols); polyol ethers (e.g., glycol ethers); and the like; andmixtures thereof with one another and/or with other organic solventcompound(s). Additions can be made in any order.

In some preferred embodiments, the macrolide(s) and synergist(s) can bemixed together directly, or with an organic solvent, to form the activeingredient composition. In various embodiments, such an activeingredient composition can be added to or combined with a particle orresin or other matrix material. Regardless of the nature of acomposition produced for animal contact, the components thereof willpreferably be selected to be veterinarily acceptable for the intendeduse on or in the subject animal. Spotting solutions are also referred toas “spot-on” compositions that can provide effective pesticidalprotection by application to a single spot or line on the subjectanimal, e.g., on the back between the shoulder blades or along thespine. Such point-of-contact formulations are topically applied to lessthan 10% of the subject animal's body surface area, preferably less than5%, or about 2% or less, or about 1% or less; and typically about or atleast 0.1% of the surface area, or about or at least 0.2% or 0.5%. Theseare distinguished from general topical formulations that are intended tocover about 25-50% or more of the body surface area of the animal, e.g.:soaks, dips, rubs, sprays, and pour-on formulations.

In various embodiments of an active ingredient composition, the ratio ofthe concentrations by weight of the synergist component to pesticidalmacrolide component can be greater than 1. In some embodiments, theratio can be at least about 1.5:1, 2:1, or 2.5:1. In some embodiments,the ratio can be from about 2:1 up to about 10:1 or up to about 5:1. Insome embodiments, weight ratios of about 1.5:1 to about 2.5:1 arepreferred, with about 2.25:1 being considered particularly useful; theseratios are considered especially useful for glycone macrolide-containingcompositions. In some embodiments of aglycone macrolide-containingcompositions, weight ratios of about 2.5:1 to about 4:1 are preferred,with about 3.5 being considered particularly useful.

In some embodiments, an active ingredient composition hereof can includepest attractant(s), pest juvenilizing hormone(s), and/or otherpest-affective substance(s); dyes, pigments, colorants; chelants,anti-oxidants; fragrance; and/or skin-benefit agents such as vitamins,emollients, waxes, and the like. Fragrance can be provided by inclusionof essentially oils, e.g., orange oil, lemon oil, etc., or by inclusionof a terpene such as D-limonene or a fragrant ester. In someembodiments, an active ingredient composition hereof can include ananimal licking- or chewing-aversion agent, e.g., a bitter-tastingcomponent such as quinine or denatonium benzoate or a pain-inducingcomponent such as capsaicin.

Resin-Based Articles

As noted above, point-of-contact pesticide technologies includeimpregnated ear tags, impregnated “hang-tags” attached to another unitsuch as an identification tag or halter, and spotting compositions suchas spotting solutions, and also includes, e.g., pesticide-impregnated:identification medallions or badges, pesticide-impregnated collars,bands, films, strips, or patches, and pesticide-delivering adhesivestrips or patches, and the like.

In various preferred embodiments, an active ingredient composition ofthe present invention can be present within, e.g. impregnated into, apolymeric material, from which the active ingredient composition can bereleased. Such a polymeric material, referred to herein in variousembodiments as a “resin base,” can be shaped in the form of an article,e.g., an ear tag, from which the active ingredient composition can bereleased. Other examples of such articles include hang tags, medallions,badges, collars, bands, films, and adhesive strips or patches. Thepolymeric material/resin base can comprise a plastic or elastic (e.g.,rubber) as the body of the article, which material serves a matrix fromwhich the release can take place. The impregnation can be accomplishedby any number of suitable means, such as, but not limited toco-extrusion or compounding; though in some embodiments, a polymermaterial or article can be contacted with an active ingredientcomposition to permit it to absorb the composition. The resin base iscapable of allowing the active ingredient composition, or at leastpesticidal macrolide(s) thereof, to be released. Preferably, the resinbase is capable of allowing the pesticide compositions to be slowlyreleased from the resin base over an extended period of time, such asseveral months. Preferably, the impregnated resin base is substantiallyodorless.

The impregnated resin base is formed by suitable means, such asinjection molding or profile extrusion and stamping processes, into adesired shape such as, but not limited to an ear tag. The exact shapeand dimensions of the ear tag are not thought to be critical to thesuccess of the present invention. Instead, in the case of such an eartag or similar article, an important feature is that the ear tag is ableto touch the subject animal's skin (epidermis and/or epidermal hair) bypoint-of-contact so as to permit the insecticide composition to beapplied to the animal. The ear tag is preferably fastened to at leastone of the animal's ears in any number of conventional ways. In onepreferred embodiment, the ear tag can be fastened to either the front orthe back of the ear by attachment to an inert, polyurethane, male buttonthat is used to pierce the ear of the animal.

The resin base employed can be thermosetting or thermoplastic, althoughthe latter is more readily employed in the manufacture of an ear tag ofthe present invention. Examples of suitable substances are polyolefins(e.g., polyethylene, polypropylene and copolymers of ethylene andpropylene); halogenated polyolefins (e.g., chlorinated polyethylene);polyacrylates (e.g., polymers and copolymers of methyl acrylate, ethylacrylate, methyl methacrylate and ethyl methacrylate); polymers of vinylcompounds (e.g., polystyrene and polymerized divinylbenzene); polyvinylhalides (e.g., polyvinyl chloride); polyvinyl acetals (e.g., polyvinylbutyryl); polyvinylidene compounds (e.g., polyvinylidene chloride);synthetic and natural elastomers (e.g., rubber obtained from Heveabrasiliensis), cis-1,4-polyisoprene, acrylonitrile-butadiene copolymers,polybutadiene styrene-butadiene copolymer (SBR); urea-formaldehyde andmelamine-formaldehyde resins; epoxy resins (e.g., polymers ofpolyglycidyl ethers of polyhydric phenols); cellulose plastic (e.g.,cellulose acetate, cellulose butyrate and cellulose nitrate); andpolyurethanes. It should be noted that the choice of the resin base willdepend both on the particular active ingredient mixture with which it isto be formulated and the conditions under which the final formulationwill be employed. To exhibit greatest pesticidal effect, the resin baseis preferably insoluble in water and presents a hydrophobic surface,thus resisting the absorption of moisture on its surface which coulddilute the active ingredients. In some preferred embodiments, a nitrilebutadiene rubber (NBR) can be used.

Preferably, the resin base may include a polymer or a copolymer of avinyl compound, for example, polyvinyl halides (e.g., polyvinyl chlorideand polyvinyl fluoride); polyacrylate and polymethacrylate esters (e.g.,polymethyl acrylate and polymethyl acrylate and polymethylmethacrylate); and polymers of vinyl benzenes (e.g., polystyrene andpolymer polymerized vinyl toluene). Because it possesses desirablephysical properties with desirable release rate characteristics for theinsecticide, one of the preferred macromolecular substances is a polymerof vinyl chloride (e.g., PVC), which can in some embodiments be combinedwith an NBR or other resin modifier.

It is generally important to include a plasticizer in the resin base inorder to permit satisfactory tag production by use of common commercialmethods, e.g., automated manufacturing processes, although resin-basedproducts without a plasticizer can be prepared in some embodimentshereof. Examples of plasticizers are phthalates (e.g., di(2-ethylhexyl)phthalate, diethylglycol phthalate, dioctyl phthalate, diphenylphthalate, dicyclohexyl phthalate, dimethyl phthalate, diethylphthalate, dihexyl phthalate, di(2-ethylhexyl) isophthalate, anddi(2-ethylhexyl) hexahydrophthalate); sebacates (e.g., di(2-ethylhexyl)sebacate, dipentyl sebacate, n-butyl benzyl sebacate, dimethyl sebacate,and dibenzyl sebacate); adipates (e.g., isobutyl adipate,di(2-ethylhexyl) adipate, dicapryl adipate, dioctyl adipate and dinonyladipate); citrates (e.g., acetyltributyl citrate and acetyl triethylcitrate); succinates; azelates; stearates; and trimellitates. Othercompatible plasticizers are, for example, hydrogenated polyphenols;alkylated aromatic hydrocarbons; polyester plasticizers, for example,polyesters of polyols, such as hexanediol; polycarboxylic acids, such assebacic or adipic acid, having molecular weights of about 2000; andepoxide plasticizers such as epoxidized soybean oil, epoxidized linseedoil and epoxidized tall oils (such as octyl epoxy tallate). Withoutbeing bound to a particular theory of the operation of the presentinvention, it is believed that a relatively softer resin base, asopposed to a relatively harder resin base, will enhance the delivery ofthe active ingredient composition when the ear tag contacts the animal'sbody. It is believed that higher concentrations of plasticizers, whichcause a softer resin base, enable higher release rates of impregnatedactive ingredients. In some preferred embodiments, an epoxideplasticizer can be used.

Other materials such as dyes, pigments, colorants, fluorescents,lubricants, fillers, anti-oxidants and ultraviolet stabilizers may beincluded in the formulation. For example, it has been found that thestability of the formulation is extended if amounts of 0.10% to about0.25% by weight, of each one or more suitable chemical stabilizers areincluded. For example, certain hydroxycinnamates (such as IRGANOX® 1076,octadecyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate) and benzotriazoles(such as TINUVIN® P, 2-(2′-hydroxy-5′-methylphenyl)benzotriazole) areeffective as stabilizers against heat and ultraviolet light degradation.Further examples of useful stabilizers include: poly N-vinylpyrrolidone(PNVP); polyethylene glycol (PEG); metal salts of long chain fattyacids, e.g., zinc stearate, calcium stearate; finely divided inorganicparticles, e.g., calcium carbonate, lithium-aluminum hydroxide-carbonate(see U.S. Pat. No. 5,356,567 to Tatebe et al.), or silica; and thosedescribed, e.g., in U.S. Pat. Nos. 3,407,171 to Jennings et al. and4,269,743 to Hulyalkar et al. In some embodiments, a combination of anyof these can be used. In various embodiments, hydroxycinnamate, PNVP,metal stearate, and inorganic stabilizers can be used.

In some embodiments, the formulation can include pest attractant(s),pest juvenilizing hormone(s), and/or other pest-affective substance(s).Formulations can also include animal licking- or chewing-aversion agentssuch as capsaicin or denatonium benzoate, to prevent animals fromlicking or chewing an article according to the present invention; see,e.g., U.S. Pat. No. 6,468,554.

In various embodiments, such a resin composition, containing an activeingredient composition according to the present invention, can be formedinto an article, such as an ear tag or hang tag, by any conventionalmethod known in the art, such as molding, extrusion-and-cutting, heatedpressing, and the like. Granulated resin base components, e.g.,granulated PVC et al., can be combined with the active ingredientcomposition, or its components, and the resulting combination can beformed, e.g., heated and: molded, pressed, extruded, or blow-molded toprepare an article (or part) hereof, e.g., a tag, badge, medallion,collar or band, film, adhesive strip or patch. The heating of thiscombination will be at a temperature below that of the point at whichdegradation of the components thereof begins. Examples of formationmethods useful herein include those described in U.S. Pat. Nos.4,721,064 to Denk et al., 5,294,445 to Sieveking et al., 4,581,834 toZatkos et al., and 6,758,000 to Sandt et al. An article hereof canconsist of the result of the formation process or can comprise the partresulting from the formation process and other element(s).

A tag or similar article hereof (badge, medallion, collar, etc.) can beprepared according to any desired format in which it can be affixed tothe subject animal. In some embodiments, it can be prepared as singlepiece or multi-piece (e.g., two-piece) article in which the two piecescan interact, e.g., snap together. In some embodiments, the article,e.g., a tag, can be designed to hang from a button, stud, or post, astaple, or from a ring or collar that is to be placed around, adheredto, or pierced into or through a body feature of the subject animal,e.g., a neck or an ear; it can similarly be designed to hang from anidentification tag or halter. The pesticidal article can be designed toperform one or more additional functions, e.g., as a visualidentification or security tag, a remote-detectable collar, and thelike.

In some embodiments, the thermoplastic resin can be cured, either beforeor after shaping into the final article, by use of a radiation or afree-radical curing agent, according to any method known usefultherefore in the art. In various preferred embodiments, no such curingis employed during production of the article and none is applied afterformation of the article. In contrast, in regard to thermosets, such acuring procedure is preferred in some embodiments hereof.

In various embodiments, a tag or other article or solution or othercomposition for direct application to a subject animal can comprise fromabout 1 to about 10% by weight of the pesticidal macrolide component; orat least about 2 or 5%; or from about 5% to about 8%. Theseconcentration ranges are considered particularly useful forpoint-of-contact formulations (tags, spotting solutions); and thoughalso useful for general topical formulations (soaks, rubs, sprays, andthe like), some embodiments of such general topical compositions cancontain an even lower concentration of the macrolide component, e.g.,from about 0.1 to about 10% by weight.

Thus, in various embodiments of the present invention, a method fortreating a subject animal can be performed in which an active ingredientcomposition is topically applied to the animal directly in the form ofany such pour-on, spot-on, dust, spray, and the like. The direct topicalapplication of the active ingredient compositions of the presentinvention can be accomplished in any number of conventional ways, suchas by spraying, pouring, shaking, dropping, or blowing the activeingredient composition onto the animal's body. Once applied, the activeingredient compositions of the present invention are effective over thecourse of several weeks or months, depending on the formulation type,and are particularly effective against various ectoparasites of domesticanimals, such as, but not limited to horn flies and buffalo flies. Invarious embodiments, the active composition comprising the PBO andavermectin-milbemycin compound(s) can be applied to silica, talc, orother small carrier particles in order to prepare a dust, e.g., byspraying the particles therewith.

Use of tags and similar articles and spotting solutions, dusts, andother compositions prepared according to various embodiments hereof canbe effectively employed to provide a pesticidal effect againstecdysozoan pests, e.g., ectoparasites, of cattle and other livestock,including but not limited to buffalo flies, horn flies, Melophagus keds,lice (especially Anoplus lice), and mites, e.g., ear mites and scabiesmites. In various embodiments, ear tags are surprisingly found to offerabout 12 to 16 weeks or more of effective protection against buffalo flyand horn fly infestations, even though the tag material may have onlycasual intermittent or indirect contact with the skin (epidermis orhair) of the treated animal. For example, ear tags applied to cattleears using a button of a different, non-pesticidal material (e.g.,polyurethane or metal), from which the ear tag hangs, have been foundeffective to provide such ectoparasite-protection (data not shown).

In various embodiments hereof, it surprisingly has been found thatabamectin/milbemycin-class macrocyclic pesticides are successfullydelivered to livestock through an ear tag, as shown by successfulcontrol of flies and other species, by point-of-contact application,because virtually all other uses of avermectin, ivermectin, etc. aredone by oral administration, by transdermal injection, or byglobal/general topical administration for absorption through the skin;and because these techniques depend on ingestion by the pest to kill it.Such a high level of point-of-contact activity has not been seen beforein the abamectin/milbemycin-class macrocyclic pesticides. It has alsosurprisingly been found that the synergistic effect of piperonylbutoxide with, e.g., the avermectins, speeds up the rate of killing hornflies compared with avermectin alone.

In various embodiments hereof, epoxidized soybean oil (ESO) has alsobeen found to have a synergizing activity in combination withabamectin/milbemycin-class macrocyclic pesticides, e.g., ivermectin, andcan be used in ear tag and other articles and compositions therewith.Useful concentrations thereof could be in the same range as thatdescribed herein for PBO. In various embodiments hereof, a PBO, ESO, orother synergist as described herein can be used to enhance thebioactivity of a abamectin/milbemycin-class macrocyclic compound even ifit has a non-pesticidal activity, e.g., as an antimicrobial (e.g.,antibacterial, antifungal, or antiprotist), anticancer, immunomodulator,or other agent. Thus, in some embodiments, a composition hereof can beadministered in order to treat, or can be co-administered to co-treat, acondition or disease other than parasite infestation.

EXAMPLES Example 1 A: Ivermectin Toxicity

A comparison of ivermectin formulations is made to determine theirtoxicity to horn fly (Haematobia irritans irritans) strains. Threeformulations are tested: ivermectin alone, ivermectin formulated withepoxidized soybean oil (ESO), and ivermectin formulated with piperonylbutoxide (PBO). Both pyrethroid-resistant (PY-Resistant) andpyrethroid-susceptible (PY-Susceptible) horn fly strains are tested.Contact toxicity is determined after four hours of exposure by contactwith treated filter papers, according to the Sheppard & Hinkleresistance test method for horn flies. See DC Sheppard & NC Hinkle, “Afield procedure using disposable materials to evaluate horn flyinsecticide resistance,” J. Agric. Entomol. 4:87-89 (1987). Results aresummarized in Table 1.

Table 1 presents the contact toxicity results in units of μg/cm²,computed using Log-Probit Analysis. See, e.g., V. K. Borooah, Logit andProbit (2002) (Sage Publications, Thousand Oaks, Calif., USA).

TABLE 1 Horn Fly Contact Toxicity of Ivermectin Alone or With SynergistsPY-Resistant PY-Susceptible Lethal Lethal Active Concen- SynergistConcen- Synergist Ingredient tration² Ratios³ tration Ratios Mixture¹LC₅₀ LC₉₀ SR₅₀ SR₉₀ LC₅₀ LC₉₀ SR₅₀ SR₉₀ Ivermectin 93.8 478.0 — — 165.6418.3 — — Ivermectin + 58.9 228.7 4.79 6.28 39.2 245.3 12.67 5.12 ESO(1:2) Ivermectin + 31.2 76.0 9.02 18.88 27.6 78.2 18.01 16.06 PBO (1:2)¹ESO = epoxidized soybean oil (added 2:1 w/w to ivermectin); PBO =piperonyl butoxide, technical (added 2:1 w/w to ivermectin) ²LC₅₀ andLC₉₀ = the Lethal Concentration to kill either 50% or 90%, respectively,of treated pests after 4-hour exposure. ³SR₅₀ and SR₉₀ = the SynergistRatios calculated by dividing (A) the LC₅₀ or LC₉₀, respectively, ofivermectin, by (B) the product of (B1) the corresponding LC₅₀ or LC₉₀for the mixture and (B2) the weight percent ivermectin concentration inthe mixture (33.3%); i.e., for example, SR₅₀ =LC_(50 (ivermectin))/(0.333 ×LC_(50 (mixture of ivermectin + synergist))).

These data show that, an ESO synergist formulation does increases thetoxicity of the composition over ivermectin alone (an increase of about35-75%, depending on LC measure and pesticide susceptibility), yetsubstitution of PBO for ESO surprisingly increases it yet another˜30-70%.

Example 1 B: Abamectin Toxicity

Further tests, similar to those of the Ivermectin tests described above,were performed using Abamectin compositions. The results are reportedbelow in Table 2.

TABLE 2 Horn Fly Contact Toxicity of Abamectin Alone or With PiperonylButoxide* PY-Resistant PY-Susceptible PY-Susceptible Lethal SynergistLethal Synergist versus Active Ingredient Mixture Concentrations RatiosConcentrations Ratios PY-Resitant (contact time) LC₅₀ LC₉₀ SR₅₀ SR₉₀LC₅₀ LC₉₀ SR₅₀ SR₉₀ RR₅₀ RR₉₀ (2 hour contact) Abamectin no mortality —— no mortality — — — — Abamectin + PBO (1:2) 477.1 13,614 — — nomortality — — — — Abamectin + PBO (1:4) 52.22 186.5 — — no mortality — —— — (4 hour contact) Abamectin 138.5 1,089 — — no mortality — — — —Abamectin + PBO (1:2) 8.00 11.75 51.99 278.24 48.96 88.32 — — 6.12 7.52Abamectin + PBO (1:4) 29.83 119.3 23.21 45.63 36.63 106.4 — — 1.23 0.89(8 hour contact) Abamectin 1.19 7.60 — — 37.65 175.16 — — 31.64 23.05Abamectin + PBO (1:2) 2.68 10.05 1.33 2.27 16.05 61.59 7.04 8.54 5.996.13 Abamectin + PBO (1:4) 5.58 10.44 1.07 3.64 7.45 15.99 25.27 54.771.34 1.53 *Results are in microgram/sq. cm computed using Log-ProbitAnalysis. NOTES: 1. PBO = piperonyl butoxide, technical, added toabamectin in solution at 2 or 4 parts PBO per part abamectin. 2.PY-Resistant = horn fly strain resistant to synthetic pyrethroidinsecticides. 3. PY-Susceptible = horn fly strain susceptible tosynthetic pyrethroid insecticides. 4. LC₅₀ and LC₉₀ = the LethalConcentration to kill either 50% or 90%, respectively, of treated pestsafter 4 hours' exposure by contact to treated filter papers using theSheppard and Hinkle resistance test method for horn flies. 5. SR₅₀ andSR₉₀ = the Synergist Ratios calculated as the LC₅₀ or LC₉₀,respectively, of abamectin divided by the product of the correspondingLC₅₀ or LC₉₀ for the mixture and the abamectin concentration in themixture); i.e., for the 1:2 ratio mixture, SR₅₀ =LC_(50 (abamectin))/(0.333 × LC_(50 (mixture))); for the 1:4 ratiomixture, SR50 = LC50 (abamectin)/(0.2 × LC50 (mixture)). RR50 and RR90,which are the resistance ratios calculated for the LCs of thePY-susceptible horn flies divided by the corresponding LCs for thePY-resistant horn flies.

These data show that, unexpectedly, it is the pyrethroid-resistant hornflies that appear to be much more susceptible to a synergizedcomposition according to an embodiment hereof (abamectin with PBO) thanare pyrethroid-susceptible horn flies. This increased susceptibility ofpyrethroid-resistant horn flies to abamectin shows up in the fact thatthere is no mortality of PY-susceptible flies with abamectin alone or incombination with PBO at 2 hours, and they show resistance at 4 hours andat 8 hours compared with PY-resistant horn flies. Also, the PY-resistanthorn flies show high susceptibility to abamectin alone after 8-hourcontact. Furthermore, the increased speed of kill of abamectin incombination with PBO shows up with high synergism at 4 hours withPY-resistant horn flies but not until 8 hours with PY-susceptible hornflies. An additional benefit of the combination of PBO technical withabamectin over time (see the 8 hour contact results) is that the amountof insecticide mixture needed to kill either strain of horn flies at theLC₅₀ or LC₉₀ level begins to approach equal amounts, thus unexpectedlyindicating that the PBO may be negating the effect of natural resistanceof the PY-susceptible flies to abamectin.

Example 2

A comparison of pesticidal ear tags is made to determine their activityagainst horn flies (Haematobia irritans irritans) on beef cattle. Eartags impregnated with 8% abamectin and 20% piperonyl butoxide technical,according to an embodiment hereof, are compared against commerciallyavailable: WARRIOR ear tags (40% organophosphate insecticide ear tags,available from Y-TEX Corp., Cody, Wyo., US, which are impregnated withthe 30% diazinon and 10% chlorpyrifos); and PYTHON ear tags (10%pyrethroid insecticide ear tags, available from Y-TEX Corp., Cody, Wyo.,US, which are impregnated with 10% zeta-cypermethrin and 20% piperonylbutoxide).

Tests are performed using two ear tags per head of cattle and treatedcattle are studied for a 15-week time course, with horn fly infestationbeing assayed weekly. Results are depicted in FIG. 1 as: ▪ WARRIOR eartag-treated cattle; ▴ PYthon ear tag-treated cattle; and ♦ PresentEmbodiment ear tag-treated cattle.

These data show that, starting about 7 weeks post-treatment, cattle withPYthon or WARRIOR ear tags begin to exhibit a significantly increasingincidence of horn fly infestation. By the end of the study,PYthon-treated cattle exhibit about 7% control, and WARRIOR-treatedcattle exhibit no (0%) control. In contrast, cattle-treated with eartags according to an embodiment hereof surprisingly still exhibit morethan 90% control. The 15-week average levels of control for the threetreated groups are: PYthon (78.3%), WARRIOR (70.4%), and PresentEmbodiment (98.3%)

The foregoing description is considered illustrative only of theprinciples of the invention. Furthermore, because numerous modificationsand changes will readily occur to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents that may be resorted to that fall within the scope of theinvention as defined by the claims that follow.

What is claimed is:
 1. An ear tag capable of controlling pests of domestic animals, comprising: a pesticidally effective amount of an active ingredient composition that comprises a) a macrolide component comprising an avermectin; and b) a synergist component comprising a 1,3-benzodioxole synergist compound; c) the weight ratio of the synergist component (b) to the macrolide component (a) being greater than 1; impregnated in a polymer resin base from which it can be released, wherein use of the ear tag results in at least 80% control of horn flies for 15 weeks.
 2. The ear tag according to claim 1, wherein the macrolide component comprises abamectin or ivermectin.
 3. The ear tag according to claim 1, wherein the macrolide component comprises abamectin.
 4. The ear tag according to claim 1, wherein the synergist component comprises piperonyl butoxide.
 5. The ear tag according to claim 4, wherein the piperonyl butyoxide is piperonyl butoxide technical and the weight ratio of piperonyl butoxide technical to avermectin is at least about 2:1.
 6. The ear tag according to claim 1, wherein the polymer resin base comprises a polymer selected from the group consisting of polyvinyl chloride, acrylonitrile-butadiene copolymer, polyurethane, chlorinated polyethylene, and mixtures thereof.
 7. The ear tag according to claim 1, wherein the resin base comprises, in addition to a polymer, a substance selected from the group consisting of plasticizers, stabilizers, colorants, fluorescents, and mixtures thereof.
 8. An article capable of controlling pests of domestic animals, comprising: a pesticidally effective amount of an active ingredient composition that comprises a) a macrolide component comprising a pesticidal compound of the avermectin-milbemycin class; and b) a synergist component comprising an aryl aliphatic ether-class synergist compound; c) the weight ratio of the synergist component (b) to the macrolide component (a) being greater than 1; impregnated in a polymer resin base from which it can be released.
 9. The article according to claim 8, wherein the article is any one of a tag, collar, band, film, or adhesive strip or patch.
 10. The article according to claim 8, wherein the article is an ear tag.
 11. The article according to claim 8, wherein the article comprises from about 1% to about 10% by weight of the pesticidal compound(s).
 12. The article according to claim 8, wherein the ratio (c) is about 2 or more.
 13. The article according to claim 8, wherein the macrolide component comprises abamectin or ivermectin.
 14. The article according to claim 8, wherein the macrolide component comprises abamectin.
 15. The article according to claim 8, wherein the aryl aliphatic ether-class synergist compound comprises any of the 1,3-benzodioxole synergist compounds or combinations thereof.
 16. The article according to claim 15, wherein the 1,3-benzodioxole synergist compound comprises piperonyl butoxide.
 17. An ear tag effective at controlling horn flies when worn by domestic cattle, the ear tag comprising a pesticidally effective amount of abamectin and piperonyl butoxide impregnated in a polymer resin base from which the abamectin can be released, wherein the weight ratio of piperonyl butoxide to abamectin is greater than 1:1.
 18. An ear tag according to claim 17, wherein use of the tag on domestic cattle results in 80% or better control of horn flies after 15 weeks of use.
 19. An ear tag according to claim 17, wherein use of the tag on domestic cattle results in 90% or better control of horn flies after 15 weeks of use.
 20. An ear tag according to claim 18, comprising about 8% by weight abamectin and about 20% by weight piperonyl butoxide.
 21. An ear tag according to claim 18, wherein the weight ratio of piperonyl butoxide to abamectin is greater than 2:1. 